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Regulator of calcineurin 1 controls growth plasticity of adult pancreas.
- Source :
-
Gastroenterology [Gastroenterology] 2010 Aug; Vol. 139 (2), pp. 609-19, 619.e1-6. Date of Electronic Publication: 2010 Jun 18. - Publication Year :
- 2010
-
Abstract
- Background & Aims: Growth of exocrine pancreas is regulated by gastrointestinal hormones, notably cholecystokinin (CCK). CCK-driven pancreatic growth requires calcineurin (CN), which activates Nuclear Factor of Activated T cells (NFATs), but the genetic underpinnings and feedback mechanisms that regulate this response are not known.<br />Methods: Pancreatic growth was stimulated by protease inhibitor (PI)-containing chow, which induces secretion of endogenous CCK. Expression profiling of PI stimulation was performed on Affymetrix 430A chips, and CN was inhibited via FK506. Exocrine pancreas-specific overexpression of CN inhibitor Regulator of Calcineurin 1 (Rcan1) was achieved by breeding elastase-Cre(estrogen receptor [ER]) transgenics with "flox-on" Rcan1 mice.<br />Results: CN inhibitor FK506 blocked expression of 38 genes, as confirmed by quantitative polymerase chain reaction. The CN-dependent genes were linked to growth-related processes, whereas their promoters were enriched in NFAT and NFAT/AP1 sites. Multiple NFAT targets, including Rcan1, Rgs2, HB-EGF, Lif, and Gem, were validated by chromatin immunoprecipitation. One of these, a CN feedback inhibitor Rcan1, was induced >50 fold during 1-8 hours course of pancreatic growth and strongly inhibited (>99%) by FK506. To examine its role in pancreatic growth, we overexpressed Rcan1 in an inducible, acinar-specific fashion. Rcan1 overexpression inhibited CN-NFAT signaling, as shown using an NFAT-luciferase reporter and quantitative polymerase chain reaction. Most importantly, the increase in exocrine pancreas size, protein/DNA content, and acinar proliferation were all blocked in Rcan1 overexpressing mice.<br />Conclusions: We profile adaptive pancreatic growth, identify Rcan1 as an important new feedback regulator, and firmly establish that CN-NFAT signaling is required for this response.<br /> (Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Calcineurin metabolism
Calcineurin Inhibitors
Calcium-Binding Proteins
Diet
Enzyme Inhibitors pharmacology
Esters
Feedback, Physiological
Gabexate administration & dosage
Gabexate analogs & derivatives
Gene Expression Profiling methods
Gene Expression Regulation
Guanidines
Integrases genetics
Intracellular Signaling Peptides and Proteins genetics
Male
Mice
Mice, Inbred ICR
Mice, Transgenic
Muscle Proteins genetics
NFATC Transcription Factors metabolism
NIH 3T3 Cells
Oligonucleotide Array Sequence Analysis
Organ Size
Pancreas drug effects
Pancreas growth & development
Pancreatic Elastase genetics
Protease Inhibitors administration & dosage
Receptor, Cholecystokinin A genetics
Receptor, Cholecystokinin A metabolism
Receptors, Estrogen genetics
Signal Transduction drug effects
Tacrolimus pharmacology
Time Factors
Transfection
Cell Proliferation
Cholecystokinin metabolism
Intracellular Signaling Peptides and Proteins metabolism
Muscle Proteins metabolism
Pancreas metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 139
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 20438729
- Full Text :
- https://doi.org/10.1053/j.gastro.2010.04.050